We seek to answer two questions: how do neurons become connected during development, and why do they become disconnected during neurodegenerative disease? There is a great deal of interest in developing models of neurodegenerative diseases in simple, invertebrate model systems that provide unequaled experimental power for characterizing the cellular events of a complex process and establishing its molecular genetic basis. Use of Drosophila for studies of neurodegeneration have been problematic, however, since in general they have either relied on highly artificial manipulations, such as high-level expression of mutated human genes in the fly, or have identified genes that clearly affect neuronal survival in the fly but are not related to any gene or pathway demonstrated to play a role in neurodegeneration in mammals. We have now identified a natural, adult-onset neurodegenerative syndrome of Drosophila in flies mutant for the ortholog of a gene directly implicated in human diseases including Alzheimer Disease and ALS. The protein kinase Cdk5, together with its regulatory subunit, p35, is one of the major kinases that phosphorylates cytoskeletal proteins to generate the neurofibrillary tangles that are characteristic of the "tauopathy" class of neurodegenerative diseases. Moreover, activated Cdk5 is found concentrated in degenerating tissue in the brains of Alzheimer patients, and experimental activation of Cdk5 induces degenerating lesions in the mouse brain. We have generated a null mutation of the gene encoding the fly homolog of the Cdk5 activating subunit, p35, and find that it causes adult-onset neurodegeneration of a specific portion of the Drosophila brain, the "mushroom bodies" that are the seat of learning and memory. We took advantage of the Drosophila system to ask what are the earliest defects in neurons that are fated to degenerate from loss of Cdk5 activity, and found two completely unexpected phenotypes. First, we found that Cdk5 is essential for the development of the portion of an axon where nerve impulses are initiated. Improper organization of this cellular compartment is expected to cause profound defects in the ability of a nerve cell to act in a neural circuit. It is certainly plausible that such defects play a role in the initiation or progression of Cdk5-associated neurodegeneration, but additional experiments will be necessary to test this hypothesis. Second, we found that Cdk5 controls the machinery responsible for the genetically-programmed disassembly of axons and dendrites at particular developmental stages. Here as well, the potential significance for this in pathological Cdk5-associated disassembly of neurons is clear, but additional experiments will be necessary to fully understand the link.